Osteoarthritis (OA) affects approximately 40 million people in the US and is the leading cause of disability in the aging population. Several animal models are available for the study of OA. However, the applicability of these models to the disease in humans is questionable. The applicant's broad, long-term objectives are to validate naturally occurring OA in cynomolgus monkeys as an animal model of the human disease and to examine therapies that may influence the prevalence or severity of the disease. Cynomolgus monkeys are widely used as models of coronary heart disease and osteoporosis. However, further characterization of OA in these animals is necessary before they will be adopted as models of this disease. Demonstrating a treatment effect on the prevalence and/or severity of OA in cynomolgus monkeys would provide additional support for the model. Multiple recent human epidemiological studies suggest that the incidence and progression of OA of the knee is lower in women who have taken ERT. The specific aims of this project are to determine: 1) whether long-term ERT decreases the severity of OA of the knee joints of aging, surgically postmenopausal cynomolgus monkeys; 2) the effects of long-term ERT on the turnover and volume of the subchondral and epiphyseal/metaphyseal cancellous bone of the knee joint; and 3) to further validate the monkey model as an appropriate animal model of OA by providing tissues and morphological data to collaborators to assist them in their ongoing and complementary studies of OA in these animals. The first two aims will be accomplished through detailed morphologic examinations of knee joints collected at necropsy from two completed NIH-funded clinical trials designed to determine the effects of ERT on the extent of coronary artery atherosclerosis in surgically menopausal (bilaterally ovariectomized) cynomolgus monkeys. In addition to morphological grading of articular cartilage lesions, the subchondral and epiphyseal/metaphyseal bone compartments will be examined separately in the same animals in order to determine the effects of ERT at each site. These proposed studies will provide a unique opportunity to obtain information that may support the use of ERT for the treatment of OA in aging women. These studies also will provide the opportunity for numerous other collaborating investigators to utilize this model to answer questions regarding the effects of estrogen and OA on bone composition, biomechanical properties of articular cartilage and ligaments of the knee joint and the relationship of levels of synovial fluid biomarkers to the histologic severity of OA of the knee joints.